Abstract
The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc - maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here, we show that tumor cell retention of a system xc --specific PET radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment. SIGNIFICANCE: [18F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy.See related commentary by Lee et al., p. 701.
Highlights
Mammalian cells have developed an exquisite system of biochemical processes with which to maintain redox homeostasis
We have shown that the PET radiotracer [18F]FSPG, already used in pilot clinical trials, can be used to monitor spatiotemporal changes in redox status
A key finding of this study is that [18F]FSPG tumor retention provides an index of redox status through its sensitivity to levels of intracellular cystine
Summary
Mammalian cells have developed an exquisite system of biochemical processes with which to maintain redox homeostasis. High levels of system xcÀ expression result in increased cystine influx [32] and GSH biosynthesis [33], processes that utilize intracellular glutamate as an exchange partner and biosynthetic precursor, respectively. This xcÀ/cystine–mediated shunting of glutamate away from anaplerotic reactions is thought to be the driving force behind reduced glutamine dependence observed in tumors when compared with cells grown in culture [32]. We evaluate the utility of [18F]FSPG for in vivo imaging of tumor redox status in a mouse model of ovarian cancer, and assess its potential for the detection of redox changes that occur during chemotherapy
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